""""""""Blockade ofCD40L to treat autoimmune diabetes (T1D) -a detailed mechanistic evaluation using RIP-LCMV mice"""""""". Systemic Treatment with antibody to CD40Ligand (aCD40L) can prevent autoimmunity and transplant rejection in several animals models and is currently under evaluation in clinical trials. It is known that aCD40L administration can inhibit expansion and effector functions of aggressive T lymphocytes, but additional regulatory mechanisms have been suggested based on transfer experiments, which would explain the exquisite long-term efficacy of this intervention in many experimental systems. Our preliminary observations demonstrate that CD40L blockade during activation of the autoaggressive response results in generation of ?regulatory? CD II c+/DX5+ APCs that can protect pre-diabetic recipients from disease in an autoantigen specific way. We used the well-established RIP-LCMV transgenic mouse model for virally induced autoimmune diabetes, where a viral antigen is expressed as a ?marker? self-antigen specifically in pancreatic b-cells and is target of the autoimmune response induced by infection with the same virus. Protection by such ?regulatory? APCs was mediated through selective, systemic reduction of autoaggressive CD4 and CD8 cells, but not by generalized immunosuppression. Based on these findings the present application has three long-term goals: 1. Precise characterization and phenotypic analysis of CD 11c+ regulatory APCs. 2. In vivo and in vitro effector mechanisms to achieve antigen specific tolerance (dampening of the autoaggressive response) by CD11c+ conditioned (regulatory) APCs. 3. In vitro generation of regulatory APCs and assessment of their in vivo efficacy. Ultimately, induction of ?regulatory? CD11c+ cells by blocking CD40L during immune activation might constitute a novel and efficacious pathway to achieve long-term antigen-specific tolerance.
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